title: Methotrexate pharmacokinetics in childhood acute lymphoblastic leukaemia: a prognostic value?
abstract: OBJECTIVE
  In industrialized countries, acute lymphoblastic leukaemia (ALL) is the most frequent cancer in children aged less than 15 years. High-dose methotrexate is a common component of many chemotherapeutic protocols for childhood with ALL. Our objective was to retrospectively evaluate the pharmacokinetics and plasma levels of high-dose methotrexate as it relates to event-free survival (EFS) in children with ALL.
  
  
  METHODS
  Relapsed patients and subjects in EFS were compared for MTX serum concentrations 24, 36, 48 and 72 h after the start of 24 h infusion. Clearance (Cl), area under the curve (AUC) and volume of distribution (V(d) ) of the drug were estimated by the NONMEM computer program and also compared between both groups.
  
  
  CONCLUSIONS
  Among 69 children included, 54 (78·3%) were still in EFS, whereas 15 (21·7%) relapsed. The difference between relapsed and EFS patients for the pharmacokinetic parameters studied was not significant. On the contrary, the cohort studied was representative and known prognostic factors for relapse in ALL were significantly associated with relapse.
  
  
  CONCLUSIONS
  Serum concentrations and pharmacokinetic parameters of MTX are not associated with outcome in ALL. Prognoses based on single-drug pharmacokinetic estimates within a complex multiple-agent protocol appear to be unreliable. However, therapeutic drug monitoring of high-dose methotrexate remains a useful tool for early detection of impaired elimination and for avoiding systemic toxicity.
authors.affiliation: Medical Pharmacology and Toxicology Department, Lapeyronie Hospital, University Hospital of Montpellier, Montpellier, France.
authors.forename: N
authors.initials: N
authors.lastname: Martelli
authors.forename: O
authors.initials: O
authors.lastname: Mathieu
authors.forename: G
authors.initials: G
authors.lastname: Margueritte
authors.forename: M C
authors.initials: MC
authors.lastname: Bozonnat
authors.forename: J-P
authors.initials: JP
authors.lastname: Daurès
authors.forename: F
authors.initials: F
authors.lastname: Bressolle
authors.forename: D
authors.initials: D
authors.lastname: Hillaire-Buys
authors.forename: H
authors.initials: H
authors.lastname: Peyrière
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001499:Bayes Theorem; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008727:Methotrexate / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008954:Models, Biological; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011379:Prognosis; D012008:Recurrence; D013997:Time Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate